This invention relates to a method for the preparation of certain biaryl derivatives.
Atypical beta-adrenoceptors are known to occur in adipose tissue and the gastrointestinal tract. Atypical beta-adrenoceptor agonists have been found to be particularly useful as thermogenic anti-obesity agents and as anti-diabetic agents. Compounds having a typical beta-adrenoceptor agonist activity have also been described as being useful in the treatment of hyperglycaemia, as animal growth promoters, as blood platelet aggregation inhibitors, as positive inotropic agents and as antiatherosclerotic agents, and as being useful in the treatment of glaucoma.
A UK patent application filed on Jun. 13, 1998 as GB 9812709.5 (and corresponding International patent application WO99/65877), discloses compounds of Formula (I) and pharmaceutically acceptable derivatives thereof: 
wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, C1-6alkyl, nitro, cyano, hydroxymethyl, trifluoromethyl, xe2x80x94NR6R6, and xe2x80x94NHSO2R6, where each R6 is independently hydrogen or C1-4alkyl;
R2 is hydrogen or C1-6alkyl;
X is oxygen, NH, or NC1-4alkyl;
R3 is cyano, tetrazol-5-yl, or CO2R7 where R7 is hydrogen or C1-6alkyl;
R4 and R5 are independently hydrogen, C1-6alkyl, xe2x80x94CO2H, xe2x80x94CO2C1-6alkyl, cyano, tetrazol-5-yl, halogen, trifluoromethyl, or C1-6alkoxy, or, when R4 and R5 are bonded to adjacent carbon atoms,
R4 and R5 may, together with the carbon atoms to which they are bonded, form a fused 5 or 6 membered ring optionally containing one or two nitrogen, oxygen, or sulfur atoms; and
Y is N or CH.
Briefly, in one aspect, the present invention provides a process for the preparation of a compound of Formula (IA) or a pharmaceutically acceptable salt thereof: 
wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, C1-6alkyl, hydroxymethyl, trifluoromethyl, xe2x80x94NR6R6, and xe2x80x94NHSO2R6, where each R6 is independently hydrogen or C1-4alkyl;
R2 is hydrogen or C1-6alkyl;
R3 is CO2R7 where R7 is hydrogen or C1-6alkyl;
R4 and R5 are independently hydrogen, C1-6alkyl, xe2x80x94CO2C1-6alkyl; and
Y is N or CH
comprising the step of preparing a diamide of Formula (II) or a pharmaceutically acceptable salt thereof: 
wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, C1-6alkyl, hydroxymethyl, trifluoromethyl, xe2x80x94NR6R6, and xe2x80x94NHSO2R6, where each R6 is independently hydrogen or C1-4alkyl;
R2 is hydrogen or C1-6alkyl;
R3 is CO2R7 where R7 is C1-6alkyl;
R4 and R5 are independently hydrogen, C1-6alkyl, xe2x80x94CO2C1-6alkyl; and
Y is N or CH.
In an alternative aspect, the invention provides a process for the preparation of a compound of Formula (IA): 
wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, C1-6alkyl, hydroxymethyl, trifluoromethyl, xe2x80x94NR6R6, and xe2x80x94NHSO2R6, where each R6 is independently hydrogen or C1-4alkyl;
R2 is hydrogen or C1-6alkyl;
R3 is CO2R7 where R7 is hydrogen or C1-6alkyl;
R4 and R5 are independently hydrogen, C1-6alkyl, xe2x80x94CO2C1-6alkyl; and
Y is N or CH, or a pharmaceutically acceptable salt thereof, comprising reduction of a compound of Formula (II): 
wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, C1-6alkyl, hydroxymethyl, trifluoromethyl, xe2x80x94NR6R6, and xe2x80x94NHSO2R6, where each R6 is independently hydrogen or C1-4alkyl;
R2 is hydrogen or C1-6alkyl;
R3 is CO2R7 where R7 is C1-6alkyl;
R4 and R5 are independently hydrogen, C1-6alkyl, xe2x80x94CO2C1-6alkyl; and
Y is N or CH, or a pharmaceutically acceptable salt thereof, and optionally the step of hydrolysis of the resulting ester group R7 in Formula (IA) to produce a compound of Formula (IA) wherein R7 is H.
In another aspect, the present invention provides a compound of Formula (II), wherein R1 is an aryl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, C1-6alkyl, hydroxymethyl, trifluoromethyl, xe2x80x94NR6R6, and xe2x80x94NHSO2R6, where each R6 is independently hydrogen or C1-4alkyl;
R2 is hydrogen or C1-6alkyl;
R3 is CO2R7 where R7 is C1-6alkyl;
R4 and R5 are independently hydrogen, C1-6alkyl, xe2x80x94CO2C1-6alkyl; and
Y is N or CH, or a pharmaceutically acceptable salt thereof.
As used herein, the terms xe2x80x9calkylxe2x80x9d and xe2x80x9calkoxyxe2x80x9d mean a straight or branched alkyl group or alkoxy group respectively, containing the indicated number of carbon atoms. For example, C1-6alkyl means a straight or branched alkyl containing at least 1 and at most 6 carbon atoms.
As used herein, the term xe2x80x9carylxe2x80x9d means monocyclic or bicyclic aromatic carbocyclic groups such as phenyl and naphthyl.
Preferably, R1 is phenoxymethyl or phenyl optionally substituted by one, two or three substituents selected from halogen, hydroxy, C1-6alkoxy, C1-6alkyl, hydroxymethyl and trifluoromethyl. More preferably, R1 is phenoxymethyl or phenyl substituted by a chlorine, fluorine or bromine atom or a methyl or trifluoromethyl group, which atom or group is preferably located in the meta position. Most preferably R1 is phenyl substituted by a chlorine atom located in the meta position.
Preferably, R2 is hydrogen or methyl. Most preferably R2 is hydrogen.
Preferably, R3 is bonded to the carbon atom meta to the bonded phenyl ring. In a compound of Formula (IA), R3 is preferably CO2H. In a compound of Formula (II), R3 is preferably CO2CH3.
Preferably, at least one of R4 and R5 is hydrogen. Most preferably, both R4 and R5 are hydrogen.
Preferably Y is CH.
Particularly preferred compounds, or compounds of the processes, of the invention include those in which each variable is selected from the preferred groups for each variable. Even more preferable compounds of the invention include those where each variable is selected from the more preferred or most preferred groups for each variable.
Reagents for the transformation of a compound of Formula (II) to a compound of Formula (I) include any suitable reagent for the reduction of amide carbonyl bonds, e.g. borane-ether, borane-sulfide, borane-amine complexes and also conditions which form borane in situ (for example, sodium borohydride and iodine or sulfuric acid). Suitable solvents include hydrocarbons, e.g. toluene or ethers, e.g. tetrahydrofuran. The reaction may be conveniently carried out on a solid substrate, such as a bead or standard substrate used in solid-phase synthesis. For example, a compound of Formula (II) may be attached to the solid substrate through the group R3, i.e. xe2x80x94CO2-solid substrate.
In order to form a compound of Formula (IA) wherein R7 is hydrogen, the step of reduction of a compound of Formula (II) should be followed by hydrolysis of the resulting ester group R7.
A compound of Formula (II) may be prepared by reaction of a compound of Formula (III) with a compound of Formula (IV) 
using any suitable method for forming an amide link, e.g. suitable coupling agents include diimides, e.g. diisopropylcarbodiimide, dicyclohexylcarbodiimide, or carbonyl diimidazole, hydroxytriazoles and equivalents, or chloroformates, whilst suitable solvents include esters, e.g. ethyl acetate, ethers, halogenated solvents, N-methylpyrrolidinone, acetonitrile or trifluorobenzene.
As a further aspect of the present invention, there is provided a compound of Formula (IV), wherein R2 is hydrogen or C1-6alkyl; R3 is CO2R7 where R7 is C1-6alkyl; R4 and R5 are independently hydrogen, C1-6alkyl, xe2x80x94CO2C1-6alkyl; and Y is N or CH, or a pharmaceutically acceptable salt thereof.
Compounds of Formula (III) are commercially available or may be prepared by standard methods, for example, as described in the examples herein.
Compounds of Formula (IV) may be prepared from compounds of Formula (V) 
using any suitable method for forming an amide link. For example, a compound of Formula (V) may be treated with a compound of Formula (VIII) 
using standard coupling procedures, e.g. diimide coupling agents, e.g. diisopropylcarbodiimide, dicyclohexylcarbodiimide or carbonyl diimidazole with a suitable glycine compound, e.g. N-Boc-glycine, in a suitable solvent such as esters, e.g. ethyl acetate, ethers, or hydrocarbons. P2 is a standard protecting group for a nitrogen, for example butoxy carbonyl.
Compounds of Formula (V) may be prepared by reaction of a compound of Formula (VI) with a compound of Formula (VII) according to the method of Thompson, (J. Org. Chem. 1984, 49, 5237), 
where Z is halogen or triflate, using a suitable boronic acid coupling conditions, e.g. palladium on carbon and sodium carbonate or Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium (0)), followed by reduction of the nitro group using standard methods, e.g. under hydrogen using a suitable catalyst, such as palladium on carbon, in a suitable solvent such as an alcohol, tetrahydrofuran, DME, ethyl acetate, toluene, iso-octane, cyclohexane or water or mixtures thereof, optionally at elevated temperature.
Compounds of Formula (IV) may also be conveniently prepared using a two step one-pot reaction starting from reaction of a compound of Formula (VI) with a compound of Formula (VII) under conditions described above, i.e. in the presence of a palladium on carbon catalyst, followed by reduction of the nitro group under hydrogen, using the reagents described above.
Compounds of Formula (V) may also be prepared by reaction of a compound of Formula (VII) with a compound of Formula (IX) using standard boronic acid coupling methods described above. 